The ability to detect the presence of oral cancer and to predict which oral precancer will eventuate to cancer will reduce the mortality and morbidity of this dreadful cancer, which accounts for 30,000 new cancer cases in the United States and 350,000 worldwide. Only 20% of oral precancers progress to cancer and currently there is no clinical, morphological or molecular parameter that can predict the malignant progression of oral precancers. This proposal builds on our recent data that signature transcriptome and proteomic biomarkers are present in saliva of oral cancer patients. We hypothesize that salivary transcriptome and proteomic signatures can be harnessed from saliva of progressing oral cancer patients that will distinguish them from non-progressing oral precancers. Three Specific Aims are in place to test the hypothesis. AIM 1 is to harness the salivary transcriptome and proteomic diagnostic biomarkers from oral cancer patients and patients with progressing oral precancers. AIMs 2 and 3 constitute phases II and III of EDRN detection studies to validate/train/build prediction models and testing the prediction models for saliva detection of oral cancer and progressing oral precancers respectively. The successful completion of these three Aims will constitute an important advancement of oral cancer and precancer diagnostics. We are optimistic that the salivary transcriptome and proteomic biomarkers will meet the rigor of these evaluations and emerge as highly specific, highly sensitive biomarkers for oral cancer detection as well as the early detection of oral cancer in the non- invasive biofluid, saliva. PUBLIC HEALTH RELEVANCE: This research project will lead to the discovery of saliva biomarkers that can be used for early detection of oral cancer as well as predicting if an oral precancer will become a cancer.